The compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are Factor Xa inhibitors. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, which are for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa.
Factor Xa is the penultimate enzyme in the coagulation cascade. Both free factor Xa and factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by compounds of formula I. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III. Effective factor Xa inhibition is achieved by administering the compounds either by oral administration, continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin.
Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting of the coronary (CABG) or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors resulting in the formation of life-threatening clots throughout the microvasculature of several organ systems. The indications discussed above include some, but not all, of the possible clinical situations where anticoagulant therapy is warranted. Those experienced in this field are well aware of the circumstances requiring either acute or chronic prophylactic anticoagulant therapy.
This invention is directed to the pharmaceutical use of a compound of formula I below for treating a patient suffering from a physiological disorder capable of being modulated by inhibiting the activity of Factor Xa, where formula I is as follows: 
is a bicyclic heretoaryl containing at least one nitrogen atom in the distal ring thereof to the proximal ring thereof that is attached to Z;
Z is alkylenyl;
R1 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, Rxe2x80x2O(CH2)xxe2x80x94, Rxe2x80x2O2C(CH2)xxe2x80x94, Y1Y2NC(O)(CH2)xxe2x80x94, or Y1Y2N(CH2)xxe2x80x94;
Rxe2x80x2 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl;
R2 is R3S(O)pxe2x80x94 or R3R4NS(O)pxe2x80x94;
R3 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl or optionally substituted heteroaralkenyl, or R1 and R3 taken together with the xe2x80x94Nxe2x80x94S(O)pxe2x80x94 moiety or the xe2x80x94Nxe2x80x94S(O)pxe2x80x94NR4xe2x80x94 moiety through which R1 and R3 are linked form a 5 to 7 membered optionally substituted heterocyclyl; and
R4 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or R3 and R4 taken together with the nitrogen to which R3 and R4 are attached form an optionally substituted 4 to 7 membered heterocyclyl;
X1 and X1a are independently selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl, or
X1 and X1a taken together form oxo;
X2 and X2a are H, or taken together form oxo;
X3 is H, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or X3 and one of X1 and
X1a taken together form a 4 to 7 membered cycloalkyl;
X4 is H, optionally substituted alkyl, optionally substituted aralkyl, or hydroxyalkyl;
X5, X5a and X5b are independently selected from H, R5R6Nxe2x80x94, (hydroxy, alkoxy or amino)HNxe2x80x94, R7Oxe2x80x94, R5R6NCOxe2x80x94, R5R6NSO2xe2x80x94, R7COxe2x80x94, halo, cyano, nitro or R8(O)C(CH2)qxe2x80x94, and one of X5, X5a and X5b is H, hydroxy or (H, optionally substituted lower alkyl, hydroxy, alkoxy or amino)HNxe2x80x94 that substitutes the distal ring of 
at a position alpha to a nitrogen thereof;
Y1 and Y2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y1 and Y2 taken together with the N through which Y1 and Y2 are linked form a 4 to 7 membered heterocyclyl;
R5 and R6 are independently H or optionally substituted lower alkyl, or one of R5 and R6 is H and the other of R5 and R6 is R8(O)CCH2xe2x80x94 or lower acyl;
R7 is H, optionally substituted lower alkyl, lower acyl or R8(O)CCH2xe2x80x94;
R8 is H, optionally substituted lower alkyl, alkoxy or hydroxy;
m is 0, 1, 2 or 3;
p is 1 or 2;
q is 0 or 1, and
x is 1, 2, 3, 4, or 5, or
a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAlkylxe2x80x9d means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. xe2x80x9cLower alkylxe2x80x9d means about 1 to about 4 carbon atoms in the chain which may be straight or branched. The alkyl may be substituted with one or more xe2x80x9calkyl group substituentsxe2x80x9d which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl or R9R10NCOxe2x80x94, wherein R9 and R10 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y1 and Y2 taken together with the N through which R9 and R10 are linked form a 4 to 7 membered heterocyclyl. Exemplary alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, pyridylmethyloxycarbonylmethyl.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. The alkenyl group may be substituted by one or more halo or cycloalkyl group. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group is optionally partially unsaturated or optionally substituted by one or more halo, methylene (H2Cxe2x95x90), alkyl, fused aryl or fused heteroaryl. Exemplary multicyclic cycloalkyl rings include 1-decalin, adamant-(1- or 2-)yl and norbornyl.
xe2x80x9cHeterocyclylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms. Preferred rings include about 5 to about 6 ring atoms wherein one of the ring atoms is oxygen, nitrogen or sulfur. The heterocyclyl is optionally partially unsaturated or optionally substituted by one or more alkyl, halo, aryl, heteroaryl, fused aryl or fused heteroaryl. Exemplary monocyclic rings include pyrrolidyl, piperidyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydrothiopyranyl. The thio or nitrogen moiety of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
xe2x80x9cArylxe2x80x9d means 6 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system. Exemplary aryl include phenyl or naphthyl, or phenyl substituted or naphthyl substituted with one or more aryl group substituents which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfonyl, alkylthio, alkylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused cycloalkyl, fused heterocyclyl, arylazo, heteroarylazo, R9R10Nxe2x80x94, R9R10NCOxe2x80x94 or R9R10NSO2xe2x80x94, wherein R9 and R10 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or R9 and R10 taken together with the N through which R9 and R10 are linked form a 4 to 7 membered heterocyclyl. The aryl group substituents are as defined herein. Preferred aryl groups are optionally substituted phenyl or optionally substituted naphthyl. Preferred aryl group substituents include hydrogen, alkyl, hydroxy, acyl, aryl aroyl, aryloxy, halo, nitro, alkoxy, cyano, alkoxycarbonyl, acylamino, alkylthio, R9R10Nxe2x80x94, R9R10NCOxe2x80x94 or R9R10NSO2xe2x80x94, where R9 and R10 are independently optionally substituted alkyl, aryl, aralkyl or heteroaralkyl; preferred phenyl group substituents are hydroxy, halogen, alkyl, amino.
xe2x80x9cHeteroarylxe2x80x9d means about a 5- to about a 10-membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Where the heteroaryl is a multicyclic hydrocarbon ring system then one of said ring systems is optionally partially or fully saturated. The xe2x80x9cheteroarylxe2x80x9d may also be substituted by one or more of the above-mentioned xe2x80x9caryl group substituentsxe2x80x9d. Exemplary heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thieniopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquiniolinyl and 1,2,3,4-tetrahydroisoquinolinyl. Where the heteroaryl is a multicyclic hydrocarbon ring system then it may be bonded through any of the ring systems. Preferred heteroaryl groups in the R1 substituent include benzothienyl, thienyl, thienopyridyl, isoquinolinyl and quinolinyl all of which may be optionally substituted. Preferred 
bicyclic heteroaryl groups include isoquinolinyl, quinolinyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, (1,2- or 2,3-) benzodiazinyl and imidazopyridyl.
xe2x80x9cAralkylxe2x80x9d means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
xe2x80x9cHeteroaralkylxe2x80x9d means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl moiety. Exemplary heteroaralkyl groups may contain thienyl, pyridyl, imidazolyl and pyrazinyl.
xe2x80x9cAralkenylxe2x80x9d means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl moiety. An exemplary aralkenyl group is 2-phenethenyl.
xe2x80x9cHeteroaralkenylxe2x80x9d means a heteroaryl-alkenlyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl moiety. Exemplary heteroaralkenyl groups may contain thienyl, pyridyl, imidazolyl and pyrazinyl.
xe2x80x9cHydroxyalkylxe2x80x9d means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl, Exemplary hydroxyalkyl groups include hydroxymethyl and 1-hydroxymethyl.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group in which the alkyl group is as previously described. Preferred acyls contain a lower alkyl, Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as previously described. Exemplary groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy and t-butoxy.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxy groups include phenoxy and naphthoxy.
xe2x80x9cAralkyloxyxe2x80x9d means an aralkyl-Oxe2x80x94 group in which the aralkyl groups is as previously described. Exemplary aralkyloxy groups include benzyloxy and 1- or 2-naphthylmethoxy.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
xe2x80x9cAralkylthioxe2x80x9d means an aralkyl-Sxe2x80x94 group in which the aralkyl group is as previously described. An exemplary aralkylthio group is benzylthio.
xe2x80x9cR9R10Nxe2x80x94xe2x80x9d means a substituted or unsubstituted amino group, wherein R9 and R10 are as previously described. Exemplary groups include amino (H2Nxe2x80x94), methylamino, ethylmethylamino, dimethylamino, diethylamino, pyrrolidino and piperidino.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkyl-Oxe2x80x94COxe2x80x94 group. Exemplary alkoxycarbonyl groups include (methoxy-, ethoxy- and t-butoxy)carbonyl.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94COxe2x80x94 group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.
xe2x80x9cAralkoxycarbonylxe2x80x9d means an aralkyl-Oxe2x80x94COxe2x80x94 group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cR9R10NCOxe2x80x94xe2x80x9d means a substituted or unsubstituted carbamoyl group, wherein R9 and R10 are as previously described. Exemplary groups are carbamoyl (H2NCOxe2x80x94) and dimethylcarbamoyl (Me2NCOxe2x80x94).
xe2x80x9cR9R10NSO2xe2x80x94xe2x80x9d means a substituted or unsubstituted sulfamoyl group, wherein R9 and R10 are as previously described. Exemplary groups are sulfamoyl (H2NSO2xe2x80x94) and dimethylsulfamoyl (Me2NSO2xe2x80x94).
xe2x80x9cAcylaminoxe2x80x9d is an acylxe2x80x94NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAroylaminoxe2x80x9d is an aroylxe2x80x94NHxe2x80x94 group wherein aroyl is as defined herein.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl-SO2xe2x80x94 group. Preferred groups are those in which the alkyl group is lower alkyl.
xe2x80x9cArylsulfonylxe2x80x9d means an aryl-SO2xe2x80x94 group.
xe2x80x9cAlkylenylxe2x80x9d means a methylenyl, ethylenyl or propylenyl group.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro.
A preferred embodiment of the invention is a method for treating a patient suffering from a physiological disorder capable of being modulated by inhibiting an activity of Factor Xa by administering a therapeutically effective amount of a compound of formula I.
Another preferred compound aspect of the invention is the compound of formula I wherein R1 is H, optionally substituted heteroaralkyl, optionally substituted aralkyl or optionally substituted alkyl.
Another preferred compound aspect of the invention is the compound of formula I wherein R2 is R3S(O)pxe2x80x94, and more preferred is R3S(O)pxe2x80x94 wherein p is 2.
Another preferred compound aspect of the invention is the compound of formula I wherein R3 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thienyl, optionally substituted benzothienyl, optionally substituted thienopyridyl, optionally substituted quinolinyl, or optionally substituted isoquinolinyl; more preferred R3 is optionally substituted naphthyl, optionally substituted thienyl, optionally substituted benzothienyl and optionally substituted thienopyridyl.
Another preferred compound aspect of the invention is the compound of formula I wherein R3 is 
Ra is hydrogen, alkyl, hydroxy, alkoxy, Y1Y2Nxe2x80x94, halogen, xe2x80x94CO2Rd, xe2x80x94C(O)NY1Y2, xe2x80x94(CH2)xORd, xe2x80x94(CH2)xNY1Y2, or xe2x80x94CN;
Rb and Rc are independently selected from hydrogen, hydroxy, alkoxy, Y1Y2Nxe2x80x94, halogen, xe2x80x94CO2Rd, xe2x80x94C(O)NY1Y2, xe2x80x94(CH2)xORd, xe2x80x94(CH2)xNY1Y2, xe2x80x94CN, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl or optionally substituted heteroaralkenyl, or Rb and Rc taken together with the carbon atoms through which they are linked form an optionally substituted 5 to 7 membered fused cycloalkyl, optionally substituted 5 to 7 membered fused heterocyclyl ring or an optionally substituted 6 membered fused aryl, or an optionally substituted 5 to 6 membered fused heteroaryl ring;
Rd is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl;
Y1 and Y2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y1 and Y2 taken together with the N through which Y1 and Y2 are linked form a 4 to 7 membered heterocyclyl;
Z1 is S or xe2x80x94CHxe2x95x90CHxe2x80x94; and
x is 1, 2, 3, 4, or 5.
Another preferred compound aspect of the invention is the compound of formula I wherein R3 is optionally substituted aralkenyl or optionally substituted heteroaralkenyl; more preferably optionally substituted heteroaralkenyl.
Another preferred compound aspect of the invention is the compound of formula I where when R3 is optionally substituted aralkenyl or optionally substituted heteroaralkenyl then the alkenyl moiety thereof is of the form 
Another preferred compound aspect of the invention is the compound of formula I where when R3 is optionally substituted aralkenyl or optionally substituted heteroaralkenyl then the alkenyl moiety thereof is of the formula 
wherein one of Q1 and Q2 is hydrogen, lower alkyl (more preferably methyl), or halo (more preferably fluoro or chloro) and the other of Q1 and Q2 is lower alkyl (more preferably methyl), or halo (more preferably fluoro or chloro).
Another preferred compound aspect of the invention is the compound of formula I where when R3 is optionally substituted aralkenyl then the aryl moiety thereof is halo substituted phenyl; more chloro substituted phenyl.
Another preferred compound aspect of the invention is the compound of formula I where when R3 is optionally substituted heteroaralkenyl then the heteroaryl moiety thereof is halo substituted thienyl; more preferably 2-chlorothien-5-yl.
Another preferred compound aspect of the invention is the compound of formula I wherein Z1 is xe2x80x94CHxe2x95x90CHxe2x80x94; and Rb and Rc taken together with the carbon atoms through which Rb and Rc are linked form an optionally substituted 5 or 6 membered heteroaryl ring, preferably containing at least one hetero atom which is N, or an optionally substituted 6 membered aryl ring, and wherein said substituents are preferably chloro, hydroxy or amino.
Another preferred compound aspect of the invention is the compound of formula I wherein Z1 is xe2x80x94CHxe2x95x90CHxe2x80x94; Rb is hydrogen; and Rc is an optionally substituted heteroaryl ring, preferably 5 or 6 membered heteroaryl ring, preferably containing at least one hetero atom which is N or S, or an optionally substituted 6 membered aryl ring, and wherein said substituents are preferably chloro, hydroxy or amino.
Another preferred compound aspect of the invention is the compound of formula I wherein Z1 is S (sulfur).
Another preferred compound aspect of the invention is the compound of formula I wherein Z1 is S (sulfur); and Rb and Rc taken together with the carbon atoms through which Rb and Rc are linked form an optionally substituted 5 or 6 membered heteroaryl ring, preferably containing at least one hetero atom which is N, or an optionally substituted 6 membered aryl ring, and wherein said substituents are preferably chloro, hydroxy or amino.
Another preferred compound aspect of the invention is the compound of formula I wherein Z1 is S (sulfur); Rb is hydrogen; and Rc is an optionally substituted heteroaryl ring, preferably 5 or 6 membered heteroaryl ring, preferably containing at least one hetero atom which is N or S, or an optionally substituted 6 membered aryl ring, and wherein said substituents are preferably chloro, hydroxy or amino.
Another preferred compound aspect of the invention is the compound of formula I wherein Z is methylenyl, and m is 1.
Another preferred compound aspect of the invention is the compound of formula I wherein X2 and X2a taken together are oxo.
Another preferred compound aspect of the invention is the compound of formula I wherein X1, X1a, X3 and X4 are H.
Another preferred compound aspect of the invention is the compound of formula I wherein 
is an optionally substituted isoquinolinyl; more preferred the isoquinolinyl is attached to Z at the 7-position thereof.
Another preferred compound aspect of the invention is the compound of formula I wherein 
is an optionally substituted quinolinyl; more preferred the quinolinyl is attached to Z at the 7-position thereof.
Another preferred compound aspect of the invention is the compound of formula I wherein 
is an optionally substituted quinazolinyl; more preferred the quinazolinyl is attached to Z at the 7-position thereof.
Another preferred compound aspect of the invention is the compound of formula I wherein 
is an optionally substituted moiety of formula 
and W is S, O or NR11, wherein R11 is H, alkyl, aralkyl, heteroaralkyl, or R8(O)C(CH2)qxe2x80x94, and A is independently CH or N; more preferably the moiety is bonded to Z through the ring containing W, and further preferred the moiety is bonded to Z through the ring containing W at the 2-position thereof.
Another preferred compound aspect of the invention is the compound of formula I wherein one of X5, X5a and X5b is H, hydroxy or amino that is substituted on the proximal ring of 
at a position that is adjacent to the position of the proximal ring to which Z is attached; more preferred one of X5, X5a and X5b on the proximal ring as noted is hydroxy or amino.
Another preferred compound aspect of the invention is the compound of formula I wherein one of X5, X5a and X5b that substitutes the distal ring of 
at the position alpha to a nitrogen thereof is H or (H, optionally substituted loweralkyl, hydroxy or amino)HNxe2x80x94.
Species according to the invention are selected from the group consisting of:
7-Methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide hydrochloride;
7-Methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(1-hydroxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]amide;
7-Methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]methylamide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methyl amide trifluoroacetate;
Benzo[b]thiophene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-Benzo[b]thiophene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide hydrochloride;
7-Methoxynaphthalene-2-sulfonic acid [1-(6-methoxyisoquinolin-7-ylmethyl)-2-oxo pyrrolidin-3-(S)-yl]amide trifluoroacetate;
4-(2-Chloro-6-nitophenoxy)benzene sulfonic acid [1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxo pyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
Benzo[b]thiophene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methyl amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(2-hydroxyquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methyl amide;
7-Methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methyl amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(2-hydroxyquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide;
7-Methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide;
7-Methoxynaphthalene-2-sulfonic acid [1-(2-hydroxyquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide;
7-Methoxynaphthalene-2-sulfonic acid [1-(1H-benzimidazol-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [2-(1H-benzimnidazol-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(4-aminoquinazolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(4-aminothieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [2-(6-aminothieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(7-aminothieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(7-hydroxythieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(4-aminothieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(4-hydroxythieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amide trifluoroacetate;
Benzo[b]thiophene-2-sulfonic acid [1-(4-aminothieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amide trifluoroacetate;
Thieno[3,2-b]pyridine-2-sulfonic acid [1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;
Thieno[2,3-b]pyridine-2-sulfonic acid [1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
4-Pyridin-3-yl-thiophene-2-sulfonic acid [1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
5xe2x80x2Chloro-[2,2xe2x80x2]bithiophenyl-5-sulfonic acid [2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide;
2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid [2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;
5xe2x80x2-Chloro-[2,2xe2x80x2]bithiophenyl-5-sulfonic acid [1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid [1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [1-(4-amino-quinazolin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [1-(4-amino-thieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate; and
5xe2x80x2-Chloro-[2,2xe2x80x2]bithiophenyl-5-2-sulfonic acid [1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate.
More preferred species according to the invention are selected from the group consisting of
7-Methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide trifluoroacetate;
Benzo[b]thiophene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid-[1-(1,6-diaminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid[1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate;
Benzo[b]thiophene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic acid [1-(4-aminothieno[3,2-c]pyridin-2-ylmethyl)-2-oxo-3-yl]amide trifluoroacetate;
Benzo[b]thiophene-2-sulfonic acid [1-(4-aminothieno[3,2-c]pyridin-2-ylmethyl)-2-oxo-3-yl]-amide trifluoroacetate;
5-Pyridin-4-yl-thiophene-2-sulfonic acid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate;
5-Pyridin-3-yl-thiophene-2-sulfonic acid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate;
Benzothiophene-2-sulfonic acid [1-(4-aminoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;
7-Methoxynaphthalene-2-sulfonic acid [2-oxo-1-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [2-oxo-1-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
Thieno[3,2-b]pyridine-2-sulfonic acid [2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide ditrifluoroacetate;
Thieno[3,2-b]pyridine-2-sulfonic acid [1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)yl]-amide;
5xe2x80x2Chloro-[2,2xe2x80x2]bithiophenyl-5-sulfonic acid [2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide;
2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid [2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [1-(4-amino-thieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid [1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate; and
5xe2x80x2-Chloro-[2,2xe2x80x2]bithiophenyl-5-2-sulfonic acid [1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate.
This invention also encompasses all combinations of preferred aspects of the invention noted herein.
A compound of formula I may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
A preparative embodiment according to the invention for preparing a compound of formula I wherein Ar1, R1, R2, X3, X4, X5, X5a, X5b, Z and m are as defined above, X1 and X1a are H and X2 and X2a, taken together form oxo, may be prepared by coupling a compound of formula II 
wherein X3, X4 and m are as defined above, X1 and X1a are H, X2 and X2a taken together form oxo, and P1 is an (alkyl, aralkyl or aryl) carbamate with a compound of formula III 
wherein Ar1, X5, X5a X5b and Z are as defined above, and one of X5, X5a, X5b is H, chloro, bromo or aryloxy at the position alpha to the nitrogen of the distal ring of Ar1, and L is a leaving group such as chloro, bromo, iodo, or optionally substituted lower alkylsulfonyloxy or arylsulfonyloxy, to give a compound of formula IV 
A compound of formula IV is converted to a compound of formula I by the methods herein described.
A compound of formula III may be prepared by reacting a compound of formula V, wherein X5c is H, R5R6Nxe2x80x94, R7Oxe2x80x94, 
R5R6NCOxe2x80x94, R5R6NSO2xe2x80x94, R7COxe2x80x94, halo, cyano, nitro or R8(O)C(CH2)qxe2x80x94, and wherein an amino or hydroxy group thereof are suitably protected by an amino or hydroxy protecting group, n is 0 to 2, and Ar2 is a monocyclic aryl or heteroaryl ring, with an appropriate malonic acid in a polar solvent such as pyridine or ethanol and a base such as piperidine or pyridine at reflux to give a compound of formula VI wherein R12 is H, 
X5c attached to the carboxymethylidene moiety is H, X5c attached to 
n and 
are as described above. Alternatively, a compound of formula VI may be reacted with a suitable Wittig reagent in an inert solvent such as THF to give a compound of formula VI wherein R12 is lower alkyl, 
n and 
X5c attached to the carboxymethylidene moiety or 
are as described above. When R12 is lower alkyl, the ester is hydrolyzed to the corresponding carboxylic acid, R12 is H, by an appropriate strong acid or alkali base. The corresponding acid is converted to the acid chloride using standard methods such as thionyl chloride or is converted to the mixed anhydride in a polar solvent such as acetone or THF to form an activated acyl compound. The activated acyl compound is then treated with a solution of NaN3 in water at about xe2x88x9210xc2x0 C. to about 25xc2x0 C. to yield the corresponding acyl azide. The acyl azide compound is then heated slowly in an inert solvent such as benzene or toluene at about 60xc2x0 C. to about 110xc2x0 C. then concentrated in vacuo and heated in a higher boiling inert solvent such as 1,2-dichlorobenzene or phenyl ether at about 180xc2x0 C. to about 240xc2x0 C. with a catalyst such as iodine or tributylamine to obtain a compound of formula VII, wherein X5c is H, R5R6Nxe2x80x94. 
R7Oxe2x80x94, R5R6NCOxe2x80x94, R5R6NSO2xe2x80x94, R7COxe2x80x94, halo, cyano, nitro or R8(O)C(CH2)qxe2x80x94, and wherein an amino or hydroxy group thereof are suitably protected by an amino or hydroxy protecting group, n is 0 to 2, and Ar2 is a monocyclic aryl or heteroaryl ring. Alternatively the acyl azide compound can be added directly to a high boiling inert solvent such as phenyl ether at about 190xc2x0 C. to about 240xc2x0 C. with a catalyst such as iodine or tributylamine to obtain the compound of formula VII.
A compound of formula VIII, prepared as described in Syn., 739 (1975) 
wherein X5c is H, R5R6Nxe2x80x94, R7Oxe2x80x94, R5R6NCOxe2x80x94, R5R6NSO2xe2x80x94, R7COxe2x80x94, halo, cyano, nitro or R8(O)C(CH2)qxe2x80x94, and wherein an amino or hydroxy group thereof are suitably protected by an amino or hydroxy protecting group, n is 0 to 2, and Ar2 is a monocyclic aryl or heteroaryl ring, or formula VII above, or those formulae wherein the amino or hydroxy moieties thereof are suitably protected by an amino or hydroxy protecting group, may be chlorinated using standard methods such as POCl3 or POCl3/PCl5 to obtain the following corresponding chlorinated intermediates (IX) and (X), wherein X5c, n and Ar2 are as defined 
above.
Furthermore, a compound of formula IX and formula X wherein X5c is a protected amino moiety wherein the protection is effected with an acid labile group such as acyl or dibenzylidene can be deprotected using standard methods such as a strong acid in an alcoholic solvent such as ethanol or a polar solvent such as ethyl acetate to yield the free amine which can then be chlorinated as above. Alternatively the free amine may be liberated by the action of the POCl3, but in either case the free amine may be reprotected with a suitable protecting group such as dibenzylidene.
A compound of formula XI, such as compounds of formulae IX and X, wherein Ar1, X5, X5a and X5b are as defined 
above, and one of X5, X5a and X5b is chloro at the position alpha to the nitrogen of the distal ring of Ar1, and the methyl moiety is attached to the proximal ring of Ar1, may be treated with NaBr or an arylhydroxy such as phenol and potassium hydroxide to afford a compound of formula XI wherein the chloro at the position alpha to the nitrogen of the distal ring of Ar1 is replaced by bromo or aryloxy at that position.
The methyl moiety of a compound of formula XI, wherein Ar1, X5, X5a and X5b are as defined above, provided that wherein X5, X5a and X5b is hydroxy or amino bearing a hydrogen then the hydroxy and amino are protected by appropriate hydroxy and/or amino protecting groups, may be halogenated using standard conditions such as N-halosuccinimide and benzoyl peroxide in an inert solvent such as carbon tetrachloride to give the corresponding halomethyl compound of formula III wherein L is bromo, chloro, or iodo, and one of X5, X5a and X5b is chloro, bromo or aryloxy at the position alpha to the nitrogen of the distal ring of Ar1.
Alternatively, a compound of formula III wherein is 
is 
A is CH, W is NH and Z is methylenyl, L is halo, one of X5, X5a and X5b is on the 5-member ring of 
and is a substituent as defined above or one wherein amino or hydroxy moieties thereof are suitably protected, another of X5, X5a and X5b is on the 6-member ring of 
and is a substituent as defined above or one wherein amino or hydroxy moieties thereof are suitably protected, and the other of X5, X5a and X5b is hydrogen, chloro, bromo or aryloxy and is substituted alpha to the nitrogen in the 6-member ring of 
may be prepared by reacting a compound of formula XII, formula XIII or XIIIa (prepared as 
described in J. Het. Chem., 29, 359 (1992); Bull. Soc. Chim. Belg. 301 (1970); and J. Med. Chem. 33, 2087 (1990) wherein W is NH and X6 is H, with POCl3 or POCl3/PCl5 as described above to obtain the corresponding chloro compound. A compound of formula XII or formula XIII wherein W is NH and X6 is H can be protected using standard methods such as with benzenesulfonyl chloride using a strong base such as sodium hydroxide in an halogenated solvent such as dichloromethane in the presence of a phase transfer catalyst such as tetrabutylammonium chloride to yield a compound of formula XII or I formula XIII wherein W is Nxe2x80x94SO2Ph and X6 is H. These are treated with a strong base such as sodium hydride, lithium hexamethyldisilylazide, or lithium diisopropyl amine in an inert organic solvent such as tetrahydrofuran or dimethylformamide at about xe2x88x9278xc2x0 C. to about 25xc2x0 C., followed by the addition of ethyl chloroformate to yield a compound of formula XII or formula XIII wherein W is Nxe2x80x94SO2Ph and X6 is xe2x80x94CO2lower alkyl, which in turn can be converted to a compound of formula XII or formula XIII wherein W is Nxe2x80x94SO2Ph and X6 is xe2x80x94CH2OH using standard hydride reducing agents such as lithium aluminum hydride in an appropriate organic solvent such as diethyl ether at about xe2x88x9210xc2x0 C. to about 25xc2x0 C. Then a compound of formula XII or formula XIII wherein W is Nxe2x80x94SO2Ph and X6 is xe2x80x94CH2OH may be halogenated using standard conditions such as PBr3 in an organic solvent such as diethyl ether to give a compound of formula III as defined above.
Alternatively, a compound of formula III may be prepared by condensing an appropriate beta-aryl or beta-heteroaryl amino acid of formulae XIV and XV, wherein W and X7 are as defined 
herein, with Gold""s reagent under basic conditions using sodium hydride or another equally strong base followed by an acidic work-up. The resulting compound is then processed as described above to yield a compound of formula III.
A compound of formula II as defined above is treated with a strong base such as sodium hydride, lithium hexamethyldisilylazide, or lithium diisopropyl amine in an inert organic solvent such as tetrahydrofuran or dimethylformamide at about xe2x88x9278xc2x0 C. to about 25xc2x0 C. followed by the addition of a compound of formula III above wherein one X5, X5a and X5b is substituted alpha to a nitrogen of the distal ring of 
and is hydrogen, chloro, bromo or aryloxy, and L is a good leaving group such as chloro, bromo, or iodo, to give a compound of formula IV above.
Alternatively a compound of formula IV wherein 
is 
A is CH, W is NH and Z is methylenyl, L is halo, one of X5, X5a and X5b is on the 5-member ring of 
and is a substituent as defined above or one wherein amino or hydroxy moieties thereof are suitably protected, another of X5, X5a and X5b is on the 6-member ring of 
and is a substituent as defined above or one wherein amino or hydroxy moieties thereof are suitably protected, and the other of X5, X5a and X5b is hydrogen, chloro, bromo or aryloxy and is substituted alpha to the nitrogen in the 6-member ring of 
may be prepared by alkylation of a (2-oxopyrrolidin-3-(S)-yl)-carbamic acid alkyl or aralkyl ester with propargyl bromide in the presence of a base such as sodium hydride. An alkyne that is obtained is heated (100-120xc2x0 C.) with a halopyridine optionally substituted with hydroxy, alkoxycarbonylamino, or sulfhydryl, a catalyst such as Pd(PPh3)2Cl2, copper iodide and triethylamine in a suitable solvent such as acetonitrile in a sealed vessel or in DMF for 2-20 hours. When the pyridine is substituted with a hydroxyl moiety furopyridines are isolated directly if the pyridine is substituted with an alkoxycarbonylamino moiety, additional treatment with DBU at about 60xc2x0 C. in DMF yields pyrrolopyridines. Subsequent deprotection yields the desired 2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-furopyridines or pyrrolopyridine-1-carboxylic acid alkyl esters. These compounds are sulfonylated in the normal manner (arene sulfonyl chlorides and base such as triethylamine) and in the case of furopyridines purified (HPLC) to obtain arenesulfonic acid [2-oxo-1-(furopyridinyl-methyl)pyrrolidine-3-(S)-yl]-amides generally as the TFA salts. In the case of pyrrolopyridines an additional deprotection step (such as acid for BOC protecting groups) yields arenesulfonic acid [2-oxo-1-(pyrrolopyridinyl-methyl)-pyrrolidin-3-(S)-yl]-amides.
The P1 moiety of the compound of formula IV is then removed by the appropriate deprotecting procedures known for carbamates such as strong acid, strong base or catalytic hydrogenation to give a compound of formula XVI, wherein Ar1, X5, X5a, X5b, Z and in are as defined above. The amine of 
the compound of formula XVI liberated by the removal of P1 is then coupled to a compound of formulae XVIII or XVIII
R3S(O)pHaloxe2x80x83xe2x80x83(XVIII)
or
R3R4NS(O)pHalo;xe2x80x83xe2x80x83(XVIII)
where R3, R4, and p are as defined above, and Halo is a halogen atom such as chloro, using a base such as a trialkylamine in an inert solvent such as dichloromethane, tetrahydrofuran, ether or acetonitrile at about 0xc2x0 C. to about 100xc2x0 C. in the presence or absence of an activating agent such as dimethyl aminopyridine (DMAP) to give a compound of formula XIX wherein Ar1, R1, R3, 
R4, X1, X1a, X2, X2a, X3, X4, X5, X5a, X5b, Z and m are as defined above.
Compounds represented by formula XIX wherein one X5, X5a, and X5b is substituted alpha to a nitrogen of the distal ring of 
and is bromo or chloro may be converted to the corresponding aryloxide by the use of an arylhydroxy such as phenol and a strong alkali base such as potassium hydroxide at 70xc2x0 C. to about 120xc2x0 C. The aryloxide intermediate (Y=ArOxe2x80x94) is then treated with an ammonium salt such as ammonium acetate at about 90xc2x0 C. to 180xc2x0 C. to give a compound of formula I wherein Ar1, R1, R3, R4, X1, X1a, X2, X2a, X3, X4, X5, X5a, X5b, Z and m are as defined above, and wherein one X5, X5a and X5b is substituted alpha to a nitrogen of the distal ring of 
and is NH2.
Alternatively, a compound of formula XIX wherein one X5, X5a and X5b is substituted alpha to a nitrogen of the distal ring of 
and is bromo or chloro may be treated with an arylhydroxy such as phenol and an ammonium salt such as ammonium acetate at about 90xc2x0 C. to 180xc2x0 C. to give compounds represented by formula I wherein Ar1, R1, R3, R4, X1, X1a, X2a, X2a, X3, X4, X5, X5a, X5b, Z and m are as defined above, and wherein one X5, X5a and X5b is substituted alpha to a nitrogen of the distal ring of 
and is NH2,
Alternatively, a compound of formula I may be prepared starting with a compound of formula XX. 
wherein X3, X4, P1 and m are as defined above, and P2 is alkyl, aralkyl or aryl, by reductive amination using a (heteroaryl)alkylamine of formula XXI 
wherein Ar1, X5, X5a, X5b and Z are as defined above, in an alcholic solvent such as methanol and an imine reducing reagent such as sodium cyanoborohydride or sodium triacetoxyborohydride at about 0xc2x0 C. to about 100xc2x0 C. to give the cyclic structure represented by formula IV which is then converted to a compound of formula I as described above.
A compound of formula XXI used in the reductive amination described above may be prepared by treatment of a compound of formula III wherein one of X5, X5a, X5b is H or aryloxy at the position alpha to the nitrogen of the distal ring of Ar1, and L is a leaving group such as chloro, bromo, iodo or other good leaving group with sodium azide followed by reduction using standard reducing methods such as triphenylphosphine in solvents such as water/tetrahydrofuran or catalytic reduction.
A compound of formula I in which R1 is other than H may be prepared starting with a compound of formula I wherein R1 is H by dissolving it in an inert organic solvent such as tetrahydrofuran, dioxane, or dimethyl formamide at about 0xc2x0 C. to about 100xc2x0 C. To the resulting solution is added a base such as sodium hydride or potassium carbonate and a compound of formula XXII.
R1xe2x80x94Haloxe2x80x83xe2x80x83XXII
wherein R1 is as defined above except for H and Halo is a halogen such as bromo or chloro.
A compound of formula I including an heteroaryl group containing one or more nitrogen ring atoms. preferably imine (xe2x95x90Nxe2x80x94), may be converted to the corresponding compound wherein one or more nitrogen ring atom of the heteroaryl moiety is oxidized to an N-oxide, preferably by reacting with a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.
The compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.
Where the compound of the present invention is substituted with a basic moiety, acid addition salts are formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on the activity of Factor Xa inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalides, e.g. hydroclhloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succiinate, fumarate, maleate, methylene-bis-B-hydroxynaphthoates, gentisates, mesylates, isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
According to a further feature of the invention, acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The compounds of this invention may be regenerated from the acid addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on the activity of Factor Xa inherent in the free acid are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including for example alkali and alkaline earth metal salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
Metal salts of compounds of the present invention may be obtained by contacting a hydride. hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.
The base addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Salt forms according to invention also include compounds having a quarternarized nitrogen. The quarternarized salts are formed by methods such as by alkylation of a sp3 or sp2 hybridized nitrogen in the compounds.
As will be self-evident to those skilled in the art, some of the compounds of this invention do not form stable salts. However, acid addition salts are most likely to be formed by compounds of this invention having a nitrogen-containing heteroaryl group and/or possessing an amino group as a substituent. Preferable acid addition salts of the compounds of the invention are those wherein there is not an acid labile group.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
Compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in either the (R) or (S) configuration. It will also be apparent to those skilled in the art that certain compounds of formula I may exhibit geometrical isomerism. Geometrical isomers include the cis and trans forms of compounds of the invention having an alkenyl moiety. The present invention comprises the individual geometrical isomers and stereoisomers and mixtures thereof.
Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.
The starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.